tbuckley/cabot-search huggingface dataset:
MDB-02. NUCLEAR ENVELOPE PHOSPHATASE CTDNEP1 MUTATIONS POTENTIATE AGGRESSIVE MEDULLOBLASTOMA BY TRIGGERING MYC ACTIVATION AND GENOMIC INSTABILITY
Authors: Richard Lu, Zaili Luo
Journal: Neuro-Oncology (2023)

Abstract MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a potent tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
MDB-10. EPIDEMIOLOGICAL PROFILE OF MEDULLOBLASTOMA IN MOROCCO: A 2-YEAR RETROSPECTIVE STUDY
Authors: Ouassima Erefai, Sara Sennani, Abdelmajid Soulaymani, Abdelrhani Mokhtari, Hinde Hami
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma is a malignant, invasive embryonal tumor of the central nervous system. This pathology is the leading malignancy in children, accounting for 30% of central nervous system pediatric tumors. This study aimed to present the epidemiological profile of medulloblastoma in Morocco. It was a retrospective study including all children aged 0 to 16 years and diagnosed with medulloblastoma at the pediatric hematology-oncology department of the children’s hospital in Rabat (Morocco) over two years, from January 1, 2021, to December 31, 2022. A total of 12 patients were included in the study, 7 boys and 5 girls (M/F ratio 1.4). The mean age was 9 ± 3 years. The majority (91.7%) of children were over 5 years of age. Only one child was aged 18 months. over half of the patients were from a rural areas. Most cases were living over 30 Km from the center. Among them, 40% were more than 150 km. A low socio-economic level was reported by 75% of the families. Two children were born to consanguineous parents. A familial cancer history was noted in 41.7% of patients. Clinical symptoms were dominated by headache (83.3%) and vomiting (66.7%). Regarding treatment, two patients were treated with surgery and seven with a combination of surgery, radiotherapy, and chemotherapy. During the period of study, there were no cases of death. A good outcome was noted in 91.7% of patients. Only one child received palliative care. Childhood cancer in general, and medulloblastoma in particular, is on the rise in Morocco. Given the scarcity of publications on this type of cancer in our country, a national registry is necessary for the monitoring and appropriate management of this disease.
MDB-12. TRANS-SPECIES ANALYSIS OF REPLICATION-REPAIR DEFICIENT (RRD) MEDULLOBLASTOMA AND RESPONSE TO IMMUNE-CHECKPOINT INHIBITION: AN IRRDC REPORT
Authors: Anirban Das, Nicholas R Fernandez, Adrian Levine, Kyle Smith, Evan Wang, Melissa Galati, Zoya Aamir, Jill Chung, Logine Negm, Owen Crump, Quang Trinh, Nuno M Nunes, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Lincoln Stein, Eric Bouffet, Michael Taylor, Paul Northcott, Vijay Ramaswamy, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Replication-repair deficiency (RRD) stemming from mismatch repair and polymerase-proofreading gene defects (MMRD/PPD) lead to hypermutant childhood cancers, most frequently brain tumors. While medulloblastoma is reported, the clinical, genomic and immune landscape remains unknown. METHODS We analysed the genome, methylome, transcriptome (bulk, single-nuclei) and immune-microenvironment of the largest cohort of RRD-medulloblastoma patients enrolled by the International RRD Consortium, and correlated these to clinical outcomes. RRD mice-models were used to preclinically assess response to immunotherapy. RESULTS RRD-medulloblastoma (n=40) were enriched for anaplasia (55%) and localised disease (85%). Methylation/nano-string-based subgrouping failed to classify 40%, while the remaining clustered with the SHH-subgroup. Copy-number changes were notably infrequent (&amp;lt;20%). All tumors harboured hypermutation and microsatellite instability in contrast to non-RRD controls (p&amp;lt;0.0001). Pathogenic variants were frequent in POLE/POLD1 (80%), TP53 (48%) and SHH-pathway genes (PTCH1, SUFU, SMO: 56%). Interestingly, some tumors additionally had glioma-driver alterations (ATRX, NF1: ~50%), similar to RRD cerebellar glioblastoma, but distinct from both non-RRD medulloblastoma (n=791) and hemispheric glioblastoma (n=733) controls. Moreover, although bulk-transcriptome matched non-RRD SHH-medulloblastoma, single-nuclei analyses suggested an earlier cell-of-origin potentially explaining the heterogenous phenotypes resulting from the driver mutations. Uniquely, immune analyses (gene expression and immunohistochemistry) demonstrated high intra-tumoral CD8 T-cell infiltration. Three-year progression-free survival was 60%. Outcome was worse for RRD-medulloblastoma harbouring TP53-mutation (p=0.04) and failing subgroup-classification (p=0.004). Nestin/Cre MSH2-/- POLE;p.S459F mice developing medulloblastoma recapitulated human disease and demonstrated response to anti-PD1 monotherapy. Recurrent/progressive human tumors including those harbouring TP53-mutations exhibited radiological responses to anti-PD1 monotherapy, which was associated with prolonged ongoing survival in comparison to those not treated with checkpoint-inhibitors (p=0.02). CONCLUSIONS Hypermutant RRD-medulloblastoma reveal heterogenous phenotypes due to unique spectrum of driver mutations and an early cell of origin. Their immune-hot microenvironment allows successful salvage treatment with checkpoint-inhibitors for those failing chemo-radiation, including the high-risk SHH/TP53-mutant and unclassified subgroups.
MDB-36. SONIDEGIB, GANT61, AND VELIPARIB TREATMENT BOTH ALONE AND IN COMBINATION INCREASES RADIATION SENSITIVITY IN PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Laura Price, Bonnie Lau
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which lead to negative long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue. Here, we investigate a new approach to radiation therapy relying on two classes of therapeutic agents, Sonic Hedgehog (SHH) inhibitors and Poly (ADP-ribose) Polymerase (PARP) inhibitors. The dysregulation and constitutive activation of the SHH signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity of various cancer types. PARP1 is known to play a key role in DNA damage repair, and it has previously been shown to affect the radiation sensitivity of pediatric brain cancers including high grade glioma, medulloblastoma, and ependymoma. We hypothesize that both inhibiting the SHH pathway at Smoothened (Smo) or Gli1 and inhibiting PARP1 will enhance medulloblastoma tumor cell killing following radiation therapy. We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone without radiation was sufficient to decrease tumor cell viability and self-renewal. When followed by radiation, pre-treatment with Sonidegib, GANT61, and Veliparib, both alone and in combination, resulted in further decreased tumor cell viability and self-renewal. These data suggest that inhibition of Smo, Gli1, or PARP1 alone or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
HGG-06. CHARACTERIZATION OF THE EFFECT OF THE ORAL IRON-MIMETIC GALLIUM MALTOLATE ON PEDIATRIC GLIOBLASTOMA GROWTH IN VIVO
Authors: Mona M Al-Gizawiy, Robert T Wujek, Casey J Zoss, Ryuma Tanaka, Shama P Mirza, Christopher R Chitambar, Kathleen M Schmainda
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of brain tumors, with our published studies showing that the ferrobiology of adult GBM can be exploited for therapeutic purposes. Here, we further elucidate the inhibitory effects of oral gallium maltolate (GaM) in pediatric GBM in vivo. METHODS Pediatric SJ-GBM2 cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison. RESULTS The sensitivity of the in vivo pediatric GBM xenografts to GaM was consistent with our previous in vitro work. Median overall survival was 21 days in the controls and 49 days in the treatment group (p=0.014). GaM-treated xenograft tumors grew significantly slower than control tumors (p=0.031). Histologically, xenograft tumors recapitulated the aggressive growth features of clinical specimens, such as invasive margins. Unlike adult GBM xenografts in our previous studies, pediatric GBM xenografts did not exhibit vessel normalization or a reduction in pro-angiogenic markers in response to GaM. Additionally, MIB-1% (p=0.6583) and mitotic index (p=0.7097) were not affected by treatment. Yet, transferrin receptor and H-ferritin expression patterns in GaM-treated tumors suggested cellular iron deprivation. CONCLUSION Monotherapy with GaM provides a significant survival benefit in pediatric GBM, and further studies are planned to optimize the benefit of GaM in pediatric GBM.
LGG-21. FGFR1 GENE MUTATION AS A POTENTIAL RISK FACTOR FOR SPONTANEOUS INTRACRANIAL HEMORRHAGE IN PEDIATRIC LOW GRADE GLIOMA PATIENTS
Authors: Brittany Lebert, Stephani Campion, Aaron Wagner, Maxine Gonzalez-Vega, Ana Aguilar-Bonilla, Amy Smith
Journal: Neuro-Oncology (2023)

Abstract The Fibroblast Growth Factor Receptor 1 (FGFR1) gene is the second most altered gene in pediatric LGGs and has been associated with poorer prognoses. A recent study suggested a link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGG patients, an event that can be detrimental to cognitive development and, in some cases, even fatal. The current study aimed to further confirm this link by following 49 pediatric LGG patients treated at the Arnold Palmer Hospital for Children from 2007-2022 and investigating the occurrences of spontaneous intracranial hemorrhage. We accessed their treatment course, clinical outcome, radiographic findings, and pathological findings. Genetic analysis was performed as part of their standard of care at the time of tumor resection or biopsy. Of the forty-nine pediatric LGG patients we followed, eight (16.3%) experienced spontaneous intracranial hemorrhage. Five of these eight patients (62.5%) had an FGFR1 mutation. Out of the forty-nine patients, only six of them had an FGFR1 mutation, and five out of the six (83.3%) experienced spontaneous intracranial hemorrhage at some point during treatment. The one patient that did not experience hemorrhage lacked a classic FGFR1 mutation and presented with a variant of unknown significance that has yet to be regarded as pathogenic. These findings are consistent with the aforementioned study and are significant because, to date, little is known about the tumor-specific risk factors for these spontaneous intracranial hemorrhages. Understanding the risk factors could help clinicians better predict these occurrences and potentially prevent their devastating effects.
IMMU-06. SYSTEMIC MRNA VACCINES RESET IMMUNOGENICITY AGAINST DIFFUSE MIDLINE GLIOMA
Authors: James McGuiness, Frances Weidert, Anna DeVries, John Ligon, Dingpeng Zhang, Christina Von Roemeling, Adam Grippin, Aida Karachi, Sadeem Qdaisat, Nagheme Thomas, Paul Castillo, Jianping Huang, Natalie Silver, Maryam Rahman, Eugene Hwang, Duane Mitchell, Hector Mendez-Gomez, Elias Sayour
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DIPG remains a uniformly fatal disease in dire need of new therapies. There are currently no systemic therapies with proven efficacy against these tumors. To overcome these barriers, we developed a systemic mRNA lipid particle (LP) vaccine that localizes to tumors and reticuloendothelial (RE) organs to modulate both innate and adaptive immunity against poorly immunogenic tumors like DIPG. OBJECTIVE We sought to assess whether RNA-LPs encoding for model antigens (e.g. H3K27M) would reprogram innate immunity and simultaneously elicit sustained adaptive immunity against diffuse midline glioma (DMG). RESULTS RNA-LP encoding for model antigens elicit massive recruitment of nearly all monocytes and lymphocytes to RE organs secondary to a danger response mediated by release of orchestrated cytokines (IL-12, TNF-α, IFN-α) and chemokines (CCL2, CCL4, CXCL9-10). This corresponds to increases in absolute numbers of activated DCs and T cells in the RE organs of mice and reprogramming the glioma tumor microenvironment in canines (pet dogs with spontaneous disease). In neonatal mice inoculated midline with established murine K2 gliomas, we observed that RNA-LP vaccines encoding for H3K27M (beginning at ~day 30) elicit significant long-term survivorship, which appears curative in the bulk of animals treated. While H3K27M specific constructs appeared superior, we observed improved survivorship with irrelevant mRNA species (i.e. pp65 and GFP) suggesting these tumors to be particularly sensitive to innate immune modulation. In mice with DMGs, we observed clinical symptomatology of edema/hydrocephalus followed by improvement in many animals suggesting pseudoprogression from intratumoral inflammation and remodeling. CONCLUSION RNA-LPs reprogram the tumor microenvironment of poorly immunogenic tumors in effect making them ‘hot.’ Treatment responses in murine models of advanced DMGs are encouraging. We are advancing a final RNA-LP formulation for FDA-IND submission and early phase clinical trials for DIPG through multi-institutional consortia.
OTHR-05. A LIVING EX VIVO PLATFORM FOR FUNCTIONAL, PERSONALIZED PEDIATRIC BRAIN CANCER DIAGNOSIS
Authors: Breanna Mann, Xiaopei Zhang, Noah Bell, Adebimpe Adefolaju, Morrent Thang, Rajaneekar Dasari, Krishna Kanchi, Alain Valdivia, Yang Yang, Carolyn Quinsey, Yasmeen Rauf, David Kram, Noah Cassidy, Cyrus Viziri, David L Corcoran, Stephan Rego, Yuchao Jiang, Lee M Graves, Denise Dunn, Scott Floyd, Albert Baldwin, Shawn Hingtgen, Andrew Satterlee
Journal: Neuro-Oncology (2023)

Abstract Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm which enable rapid engraftment, treatment, and analysis of fresh patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establish on OBSCs among endogenous astrocytes and microglia while maintaining the tumor’s original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and healthy tissue toxicity, generating summarized drug sensitivity scores based on therapeutic window and allowing us to normalize response profiles for a panel of FDA-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment revealed positive associations to clinical outcomes, suggesting the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.
TRLS-10. ROVER: A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Carl Koschmann, Lindsey M Hoffman, Christof M Kramm, Ashley Plant-Fox, Mohamed S Abdelbaki, Ashley Bui, Michela Casanova, Daniel A Morgenstern, Preethi Swamy, Hongliang Shi, Janet Hong, Mikael L Rinne, Susan N Chi
Journal: Neuro-Oncology (2023)

Abstract Pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors have poor prognoses. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. Diffuse midline gliomas with H3K27-altered (DMG-H3K27-altered) depend on PDGFRA signaling for tumor growth. However, no KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, including DMG-H3K27-altered. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50&amp;lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios from 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved to treat adults with advanced systemic mastocytosis in the USA, and in Europe after ≥1 prior systemic therapy. Avapritinib is also approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA, and PDGFRA D842V mutations in Europe. ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib in pediatric patients aged 2 to &amp;lt;18 years with R/R solid tumors dependent on KIT or PDGFRA signaling, including DMG-H3K27-altered. Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; the primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; the primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Avapritinib once daily will be administered in continuous 28-day cycles. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
OTHR-03. CLASSIFICATION OF BRAIN TUMORS BY NANOPORE SEQUENCING OF CELL-FREE DNA FROM CEREBROSPINAL FLUID
Authors: Ann-Kristin Afflerbach, Christian Rohrandt, Björn Brändl, Marthe Sönksen, Jürgen Hench, Stephan Frank, Daniela Börnigen, Malik Alawi, Martin Mynarek, Beate Winkler, Franz Ricklefs, Michael Synowitz, Lasse Dührsen, Stefan Rutkowski, Annika K Wefers, Franz-Josef Müller, Melanie Schoof, Ulrich Schüller
Journal: Neuro-Oncology (2023)

Abstract For exact molecular diagnosis of CNS tumors, tumor tissue obtained through surgery is usually needed. However, knowledge on the molecular tumor type beforehand might influence surgical strategies and reduce surgery-associated risks. Molecular analyses of liquid biopsies have therefore gained increasing interest in order to secure diagnosis before surgery or to replace surgery in rare instances. Moreover, the minimally invasive nature of liquid biopsies enables a tight and longitudinal tumor monitoring with potentially higher sensitivity than imaging approaches. In this study, we applied Nanopore sequencing to 129 cell-free DNA (cfDNA) samples from the cerebrospinal fluid (CSF) of brain tumor patients, with 70.5% coming from pediatric patients. We analyzed copy number variations (CNV) and methylation patterns with a recently published random forest classifier (NanoDx). Circulating tumor DNA (ctDNA) was detected and successfully classified the tumor in 45% of all technically successful samples, both in pre- and early post-surgery samples as well as in samples from &amp;gt;14 days post-surgery, often with clinically unclear residual tumor or disease relapse. In all samples containing detectable tumor DNA, CNV analysis was more frequently successful than methylation analysis with overall detection rates of 88% and 44%, respectively. CNV analysis revealed diagnostic alterations, such as C19MC amplifications in ETMR as well as Chr.1q gain and Chr.6q loss in PFA ependymoma, which are important prognostic markers. Methylation analysis also allowed the classification of tumors with balanced genomes, like craniopharyngiomas. Finally, we were able to perform longitudinal analyses and found aberrations in the CNV profiles that were private to the tumor relapse, highlighting the potential of liquid biopsies to detect potentially relevant changes of tumor biology. Our results show that Nanopore sequencing is a promising approach to establish initial tumor diagnosis and to monitor disease courses by lumbar punctures.
MDB-24. A DATA-DRIVEN APPROACH FOR THE IDENTIFICATION OF NEW SYNERGISTIC DRUG COMBINATIONS AGAINST NEURAL CANCERS
Authors: Gergana Popova, Ida Larsson, Alper Koc, Cecilia Krona, Sven Nelander
Journal: Neuro-Oncology (2023)

Abstract High-risk medulloblastomas are tumours with a poor survival prognosis (≤ 50%), which are currently treated with radiation therapy and DNA-damaging chemotherapy. The severe side effects of these treatments, including developmental problems and secondary tumours, underscore the need for new treatments with reduced toxicity. An attractive target for such therapy is the Myc-family proteins since high-risk medulloblastomas amplify either N-Myc (SHH-MB, G4-MB) or c-Myc (G3-MB). While the proteins from the Myc family themselves are often referred to as pharmacologically intractable, their levels and activity can be modulated by indirect targeting, e.g. inhibition of proteins located upstream or downstream of c-Myc/N-Myc. The diverse cellular processes and pathways that c-Myc and N-Myc are involved in, however, suggest that several Myc pathways must be interrupted simultaneously to achieve a lasting effect. To identify such multimodal interventions against Myc, we performed a principal component analysis of RNA sequencing data from patient-derived medulloblastoma cells (MB002, G3, MYC-amplified) and DAOY cells (SHH-group, no MYC amplification) that were treated with 120 small molecules. In the subsequent analysis, we focused on a selection of ~ 40 genes that represent common upstream regulators and downstream targets of either c-Myc or N-Myc. Applying a principal component analysis to these particular markers, we expect that the drugs that affect different pathways associated with c-Myc activity and are located at the opposite ends of the PC1 and PC2 axis should have a synergistic effect. Additionally, we expected that the drugs located closer to each other, which affect closely related pathways, would either have no effect or would be antagonistic. Our PCA distribution method can be used to select synergistic combinations in a manner that is easily extended to new compounds. This approach may allow fast screening of compounds for estimation of the treatment effect.